What is the role of terlipressin in treating Hepatorenal Syndrome (HRS)?

Use of Terlipressin in Hepatorenal Syndrome

Terlipressin plus albumin is the first-line pharmacological treatment for HRS-AKI (Type 1 HRS) and should be initiated immediately upon diagnosis, with a starting dose of 1 mg IV every 4-6 hours (or 2 mg/day continuous infusion) combined with albumin 1 g/kg on day 1 followed by 20-40 g/day. 1, 2

Indications and Patient Selection

• All patients meeting the current definition of AKI-HRS stage >1A should be expeditiously treated with vasoconstrictors and albumin 1
• Terlipressin is indicated for HRS-AKI (formerly Type 1 HRS), characterized by rapid progressive renal impairment with serum creatinine increasing ≥100% to >2.5 mg/dL in less than 2 weeks 2
• Terlipressin plus albumin is NOT recommended for HRS-NAKI (formerly Type 2 HRS) because recurrence after treatment withdrawal is the norm and controversial data exists on long-term clinical outcomes 1

Dosing Regimens and Administration

Initial Dosing Options

• Bolus dosing: Start with 1 mg IV every 4-6 hours (total 4-6 mg/day) 1, 2, 3
• Continuous infusion (preferred): Start with 2 mg/day as continuous IV infusion, which provides equal efficacy with lower total daily doses and significantly fewer ischemic side effects compared to bolus dosing 1, 3, 4

Dose Escalation Protocol

• If serum creatinine does not decrease by at least 25% from baseline after 2-3 days, increase the dose in a stepwise manner 1, 2, 3
• For bolus dosing: Escalate to 2 mg every 4-6 hours 1, 3
• Maximum dose: 12 mg/day regardless of administration method 1, 3
• Continue treatment until serum creatinine decreases below 1.5 mg/dL or for a maximum of 14 days 2, 3

Mandatory Albumin Co-Administration

• Albumin must always be given concurrently with terlipressin, as terlipressin alone is significantly less effective (25% response rate vs 77% with combination) 3, 4
• Albumin dosing: 1 g/kg IV (maximum 100 g) on day 1, followed by 20-40 g/day IV until treatment completion 1, 2, 3
• Serial measurement of central venous pressure or other measures of central blood volume can help prevent circulatory overload and optimize albumin dosing 1

Pre-Treatment Assessment and Contraindications

Required Screening

• Obtain baseline electrocardiogram to screen for ischemic heart disease before starting treatment 1, 3
• Check baseline oxygen saturation—do not use if SpO₂ <90% on room air or supplemental oxygen per FDA warning 3, 5
• Assess ACLF grade and volume status 3

Absolute Contraindications

• SpO₂ <90% on room air or supplemental oxygen 3
• Active coronary, peripheral, or mesenteric ischemia 3
• Serum creatinine >5 mg/dL 3

Monitoring During Treatment

• Check serum creatinine daily looking for ≥25-30% reduction by days 3-4 3
• Monitor vital signs including pulse oximetry every 2-4 hours 3
• Monitor for ischemic complications (occur in ~12% of patients): abdominal pain, chest pain, digital ischemia, arrhythmias 3, 4
• Monitor for respiratory failure, which occurs in 14-30% of patients 1, 3
• A sustained increase in mean arterial pressure of ≥5-10 mmHg at day 3 predicts treatment response 3, 4

Treatment Response Definitions

• Complete response: Serum creatinine returning to within 0.3 mg/dL of baseline value 1, 3
• Partial response: Regression of AKI stage with serum creatinine ≥0.3 mg/dL from baseline or ≥25% reduction in creatinine 1, 3
• Discontinue if no response (creatinine reduction <25%) by day 14 3, 4

Efficacy Data

• Pooled analysis of phase 3 trials showed HRS reversal was significantly more frequent with terlipressin versus placebo (27% vs 14%; P = 0.004) 6
• Meta-analysis demonstrated pooled odds ratio of HRS reversal was 8.09 (95% CI, 3.521-18.59; p=0.0001) for terlipressin versus placebo 7
• Individual randomized trials have shown HRS reversal rates of 70% with terlipressin plus albumin 8, 9

Predictors of Treatment Success

• Baseline serum creatinine <3 mg/dL (better outcomes with mild-moderate AKI) 4
• Baseline bilirubin <10 mg/dL 3, 4
• Child-Pugh score <13 and lower MELD score 4
• Mean arterial pressure increase ≥5-10 mmHg by day 3 3, 4
• Absence of known precipitating factors for HRS 6

Alternative Vasoconstrictors

Noradrenaline (Second-Line)

• Noradrenaline can be an alternative to terlipressin, but requires a central venous line and ICU admission in several countries 1
• Dosing: Start at 0.5 mg/hour (or 5 μg/min) continuous IV infusion, titrate up to 3 mg/hour (or 10 μg/min) to achieve MAP increase >10 mmHg above baseline 1, 3, 4
• Similar response rates of 39-70% compared to terlipressin 3

Midodrine Plus Octreotide (Third-Line)

• Midodrine plus octreotide plus albumin should only be used when terlipressin or noradrenaline are unavailable, as its efficacy is much lower than terlipressin 1, 2, 4
• Randomized trial showed significantly lower HRS reversal rate with midodrine/octreotide (28.6%) versus terlipressin (70.4%), P = 0.01 9
• Dosing: Midodrine 7.5 mg orally three times daily (up to 12.5 mg three times daily) plus octreotide 100-200 μg subcutaneously three times daily 1, 2, 4

Administration Setting

• Terlipressin can be safely administered via peripheral IV line on a regular ward without requiring ICU-level monitoring in most patients 3
• ICU monitoring is required for patients with ACLF grade 3 (≥3 organ failures) due to increased risk of respiratory failure 3
• The decision to transfer to higher dependency care should be case-based 1

Management of Treatment Recurrence

• In cases of HRS-AKI recurrence upon treatment cessation, a repeat course of therapy should be given 1

Safety Profile and Adverse Events

• Adverse events include ischemic and cardiovascular events occurring in approximately 12% of patients 1, 3
• Respiratory failure occurs in 14-30% of patients 1, 3
• According to the type and severity of side effects, treatment should be modified or discontinued 1
• Terlipressin increases mean arterial pressure by approximately 16.2 mmHg and decreases heart rate by approximately 10.6 beats/minute 5
• Most side effects are transient and self-limiting, including crampy abdominal pain and cardiac arrhythmias 8

Mechanism of Action

• Terlipressin is a synthetic vasopressin analogue with twice the selectivity for vasopressin V1 receptors versus V2 receptors 5
• It acts as both a prodrug for lysine-vasopressin and has pharmacologic activity on its own 5
• Terlipressin increases renal blood flow by reducing portal hypertension, increasing effective arterial volume and mean arterial pressure 5, 10
• The improvement in hemodynamics is associated with increased glomerular filtration rate and deactivation of vasoconstrictor and sodium-conserving hormones 10

Role in Liver Transplantation

• Liver transplantation is the definitive treatment for HRS-AKI 2
• Treatment of HRS before transplantation with vasoconstrictors may improve outcomes after transplantation 2
• Patients with HRS who show improvement in renal function with terlipressin and albumin have excellent post-transplantation outcomes similar to patients without HRS 10